Kaletra pills 200mg+50mg, 120pcs

Composition

Each tablet contains: Active ingredients: Lopinavir-200 mg, ritonavir-50 mg; Excipients: copovidone K 28 – 426.9 mg; sorbitan laurate-41.95 mg; colloidal silicon dioxide-6.0 mg; second layer: sodium oxaryl fumarate-6.15 mg; colloidal silicon dioxide-4.0 mg; Film coating: Opadray ® II pink 85 F 14399-15.0 mg (polyvinyl alcohol-40.00%, titanium dioxide-24.85%, talc-14.80%, macrogol 3350-20.20%, iron oxide red dye E172-0.15%.

Pharmacological action

Kaletra® is a combination drug that contains lopinavir and ritonavir.

Lopinavir is an inhibitor of HIV-1 and HIV-2 proteases of the human immunodeficiency virus (HIV) and provides antiviral activity of the drug. Inhibition of HIV proteases interferes with the synthesis of viral proteins and prevents the cleavage of the gag-pol polypeptide, which leads to the formation of an immature and unable to infect virus.

Ritonavir inhibits the CYP3A-mediated metabolism of lopinavir in the liver, which leads to an increase in the concentration of lopinavir in blood plasma. Ritonavir is also an HIV protease inhibitor.

Resistance

HIV-1 isolates with reduced sensitivity to lopinavir were selected in vitro. The presence of ritonavir did not affect the isolation of lopinavir-resistant viruses in vitro.

In the phase III study, viral isolates from each patient with a plasma HIV RNA concentration of more than 400 copies/ml at weeks 24,32,40, and/or 48 were analyzed during the antiretroviral (ARV) treatment of previously untreated patients. All 37 evaluated patients treated with lopinavir / ritonavir showed no signs of genotypic or phenotypic resistance to lopinavir/ritonavir. No resistance to lopinavir/ritonavir was detected in children who had not previously received ARV therapy.

In phase II clinical trials of Kaletra® among 227 HIV-infected patients who received and did not receive previously antiretroviral therapy,4 out of 23 patients with virologic ineffectiveness of therapy (HIV RNA >400 copies/ml) showed a decrease in sensitivity to lopinavir after 12-100 weeks of Kaletra® therapy; 3 out of 4 patients previously received one of the HIV protease inhibitors (nelfinavir, saquinavir or indinavir),1 out of 4 patients – combination therapy with HIV proteases (indinavir, saquinavir and ritonavir).

All 4 patients had at least 4 mutations associated with resistance to HIV protease inhibitors before starting Kaletra therapy. Further increase in the viral load was associated with the appearance of additional mutations associated with the development of resistance to HIV protease inhibitors.

However, these data are not sufficient to identify mutations responsible for the development of resistance to lopinavir.

Cross-resistance

To date, there is insufficient data on the development of cross-resistance during lopinavir/ritonavir therapy. The virological response to lopinavir/ritonavir therapy was altered in the presence of three or more of the following amino acid substitutions in the HIV protease gene: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.

The clinical significance of reduced sensitivity to lopinavir in vitro was studied based on the virological response to lopinavir/ritonavir therapy depending on the initial genotype and phenotype of the virus in 56 patients with HIV RNA above 1000 copies/ml who had previously received therapy with nelfinavir, indinavir, saquinavir or ritonavir (study M 98-957).

In this study, patients were given lopinavir / ritonavir at one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Prior to initiation of EC50 therapy (the drug concentration required to inhibit the replication of 50% of viruses) of lopinavir for 56 virus strains was 0.5-96 times higher than EC50 for wild-type virus. 55% (31/56) of the virus strains showed a decrease in sensitivity to lopinavir by more than 4 times, while the average decrease in sensitivity to lopinavir among 31 strains was 27.9 times.

After 48 weeks after initiation of therapy with lopinavir/ritonavir with efavirenz and nukleozidnykh reverse transcriptase inhibitors, the concentration of HIV RNA ≤400 copies/ml was detected in 93% (25/27),73% (11/15) and 25% (2/8) of patients whose initial sensitivity to lopinavir has been reduced to ≤10,10-40 times and ≥40, respectively. In these groups, the concentration of HIV RNA was < 50 copies / ml. 81% (22/27),60% (9/15) and 25% (2/8) of patients, respectively.

However, additional studies are needed to identify mutations that contribute to the development of resistance to lopinavir.

Pharmacokinetics

The pharmacokinetics of lopinavir in combination with ritonavir were studied in healthy volunteers and HIV-infected patients; no significant differences were found between the two groups. Lopinavir is almost completely metabolized by the CYP3A isoenzyme. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma concentrations.

When using lopinavir/ritonavir at a dose of 400/100 mg twice a day, the average steady-state plasma concentrations of lopinavir in HIV-infected patients were 15-20 times higher than those of ritonavir, and the plasma concentration of ritonavir was less than 7% of the concentration when taking ritonavir at a dose of 600 mg twice a day. The EC50 of lopinavir in vitro is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

When taking food, the plasma concentrations of lopinavir and ritonavir after taking two 200/50 mg tablets are equivalent to three 133/33 mg capsules with minimal pharmacokinetic variability.

Suction

In a pharmacokinetic study involving HIV-positive patients (n=19), when taking 400/100 mg of lopinavir/ritonavir twice daily with food for three weeks, the average value of the maximum plasma concentration of lopinavir (Cmax) was 9.8 ± 3.7 mcg/ml, observed approximately four hours after taking the drug. The average steady-state concentration before the morning dose was 7.1 ± 2.9 mcg / ml and the minimum concentration within the dosage interval was 5.5 ± 2.7 mcg / ml.

The area under the concentration-time curve (AUC) of lopinavir within 12 hours after taking the drug averaged 92.6 ± 36.7 µg / h / ml. Absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established.

Distribution

At steady state, approximately 98-99% of lopinavir is bound to plasma proteins. Lopinavir binds to alpha-1-acid glycoprotein (ACG) and albumin, however, lopinavir has a higher affinity for ACG. At steady state, the binding of lopinavir to plasma proteins remains constant in the range of registered concentrations created after taking 400/100 mg of lopinavir / rntonavir twice a day, and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

In vitro studies have shown that lopinavir mainly undergoes oxidative metabolism involving the cytochrome P450 system of hepatocytes, mainly under the influence of the CYP3A isoenzyme. Ritonavir is a potent inhibitor of the CYP3A isoenzyme, which inhibits the metabolism of lopinavir, resulting in increased plasma concentrations of lopinavir. After a single dose of 400/100 mg of lopinavir / ritonavir (with 14C – labeled lopinavir),89% of the radioactivity was provided by the original drug. At least 13 oxidative metabolites of lopinavir have been identified in humans.

Ritonavir is able to induce cytochrome P450 isoenzymes, which leads to the induction of its own metabolism. During long-term use, lopinovir concentrations before the next dose decreased over time, stabilizing after approximately 10-16 days.

Deduction

After taking 400/100 mg of 14C-lopinavir/ritonavir after eight days, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the 14C-lopinavir dose are detected in the urine and feces, respectively. Moreover, unchanged lopinavir is 2.2 and 19.8%, respectively. After prolonged use, less than 3% of the lopinavir dose is excreted unchanged through the kidneys. The clearance (CL/F) of lopinavir when taken orally is 5,98 +/- 5,75 l/h.

Indications

Treatment of HIV infection in adults and children over 3 years of age in combination therapy.

Contraindications

With caution

Side effects

Adult patients The most common side effect associated with lopinavir/ritonavir use was mild to moderate diarrhea. Side effects possibly causally related to the use of the drug, both clinical and laboratory, are listed below with an indication of frequency (very often ≥1/10, often ≥1/100, but <1/10, infrequently ≥1/1000, but <1/100, rarely ≥1/10000, butFrom the immune system

• Infrequently: hypersensitivity reactions.
• Rare: immune recovery syndrome.
• From the digestive system
• Very common: diarrhea.
• Common: abdominal pain, flatulence, nausea, vomiting, irregular stools.
• Infrequently: dyspepsia, abdominal discomfort, dry mouth, hemorrhagic enterocolitis, fecal incontinence, gastritis, gastroesophageal reflux, pancreatitis, hepatitis.
• Rare: dysphagia, lower abdominal pain, constipation, duodenitis, enterocolitis, enteritis, belching, esophagitis, stomach ulcers, hemorrhoids, mouth ulcers, periodontitis, rectal bleeding, stomatitis, hepatomegaly, cholecystitis, jaundice, liver steatosis and liver pain. Less than 2% had cholangitis.

Nervous system disorders:

• Common: headache.
• Infrequently: insomnia, paresthesia, decreased libido, depression, sleep disturbance, restlessness, nervousness, dizziness, peripheral neuropathy, drowsiness, taste distortion.
• Rarely: agitation, confusion, emotional lability, disorientation, thinking disorders, amnesia, ataxia, dyskinesia, encephalopathy, extrapyramidal syndrome, facial nerve paresis, muscle tone, migraine, neuropathy, loss of taste and tremor. Less than 2% had: apathy, cerebral infarction, and seizures.

From the cardiovascular system:

• Infrequently: vascular disorders.
• Rare: high blood pressure, angina pectoris, atrioventricular block, myocardial infarction, palpitation, tricuspid valve insufficiency, deep vein thrombosis, thrombophlebitis, varicose veins and vasculitis. Less than 2% had atrial fibrillation and orthostatic hypotension.

Skin and subcutaneous fat disorders:

• Common: lipodystrophy.
• Infrequently: rash, acne, alopecia, allergic dermatitis, maculopapular rash, pruritus and hyperhidrosis.
• Rare: dry skin, eczema, idiopathic capillaritis, exfoliative dermatitis, facial edema, nail structure disorders, seborrhea, skin discoloration, striae, skin ulcers. Less than 2% had hypertrophy of the skin.

From the musculoskeletal system

• Infrequently: myalgia, arthralgia,
• Rare: osteoarthritis, low back pain and bone necrosis, joint disease. Less than 2% had muscle weakness. Metabolic and endocrine disorders
• Infrequently: dehydration, diabetes mellitus, Itsenko-Cushing syndrome, obesity, anorexia, weight loss or increase.
• Rarely: male hypogonadism, decreased or increased appetite, hyperamylasemia, hyperlipazemia, hyperurekemia, hypophosphatemia, hypocholesterolemia, hypovitaminosis and hypothyroidism, lactic acidosis, lipomatosis.

From the side of the kidneys and urinary tract:

• Rare: hematuria, nephrolithiasis, nephritis and abnormalities in laboratory urine parameters, changes in the smell of urine.

From the side of the reproductive system:

• Infrequently: erectile dysfunction.
• Rare: amenorrhea, ejaculation disorder, breast enlargement, gynecomastia, menorrhagia.

Respiratory system disorders:

• Infrequently: bronchitis.
• Rare: cough, shortness of breath, pulmonary edema. Less than 2% had bronchospasm.

From the side of the blood system and hematopoietic organs:

• Rare: anemia, leukopenia, and lymphadenopathy.

From the side of the senses:

• Infrequently: tinnitus.
• Rarely: visual disturbances, hyperacusis, and dizziness, balance disorders.

Infections:

• Rare: bacterial infection, bronchopneumonia, inflammation of the subcutaneous fat, folliculitis, furunculosis, gastroenteritis, otitis media, perineal abscess, pharyngitis, rhinitis, sialoadenitis, sinusitis, and viral infection (including influenza).

Benign, malignant, and unspecified neoplasms (including cysts and polyps):

• Rare: neoplasms (including benign skin neoplasms), cysts.

Common:

• Often: asthenia.
• Infrequently: pain, chest pain, fever, swelling, malaise.
• Rarely: chills, peripheral edema, chest pain, splenomegaly.

Changes in laboratory parameters:

• Very often: increase in the concentration of total cholesterol, triglycerides; increase in the activity of gamma-glutamyltranspeptidase (GTTP);
• Often: Increase in glucose concentration, deviations from the norm of “liver” tests, increase in the activity of serum aspartate aminotransferase (ACT), alanine aminotransferase (ALT), amylase.
• Infrequently: increased total bilirubin concentration, abnormal hormone concentration tests and other laboratory tests, increased lipase activity, decreased creatinine clearance, and decreased glucose tolerance.
• Rare: neutropenia, increased alkaline phosphatase activity. Less than 2% of patients had: increased uric acid concentration, increased creatine phosphokinase activity, decreased concentrations of inorganic phosphorus and hemoglobin.

The profile of adverse events in children was similar to that in adults. The most common symptoms were taste distortion, vomiting, diarrhea, and rash. Viral infections, constipation, pancreatitis, hepatomegaly, dry skin, fever, increased activated partial thromboplast time, decreased hemoglobin, decreased platelet count, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SHPT/ALT, increased CGOT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils were also frequently observed. Cases of toxic epidermal necrolysis, hepatitis, Stevens-Johnson syndrome, erythema multiforme and bradyarrhythmia have also been reported with lopinavir/ritonavir.

Interaction

Lopinavir / ritonavir is an in vitro and in vivo inhibitor of the CYP3A isoenzyme. Concomitant use of lopinavir / ritonavir and drugs primarily metabolized by the CYP3A isoenzyme (for example, dihydropyridine slow calcium channel blockers, HMG-CoA reductase inhibitors, nmmunosuppressants, and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of other drugs whose therapeutic or side effects may increase or last. In drugs that are extensively metabolized by the CYP3A isoenzyme and have a high presystemic metabolism, when taken simultaneously with lopinavir/ritonavir, a significant increase in AUC (more than 3-fold) is more common. Drugs that are contraindicated precisely because of undesirable interactions and the possibility of developing serious side effects are presented in the section “Contraindications”. Lopinavir / ritonavir is metabolized by the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs that induce the CYP3A isoenzyme may reduce plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes were not observed when co-administered with ketoconazole. Concomitant use of lopinavir / ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir. Drugs for the treatment of HIV-nucleoside reverse transcriptase inhibitors (NRTIs)Stavudip and lamivudine did not change the pharmacokinetics of lopinavir when lopinavir / ritonavir was co-administered with stavudine and lamivudine. Didanosine It is recommended to take didanosine on an empty stomach; therefore, in combination with didanosine, lopinavir/ritonavir tablets should be taken separately from food. Zidovudine and abacavir Lopinavir / ritonavir induces glucuronidation, so the drug can reduce the plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown. Tenofovir studies have shown that lopinavir / ritonavir increases the concentration of tenofovir in blood plasma. The mechanism of this interaction is unknown. Patients taking lopinavir / ritonavir and tenofovir should be monitored for tenofovir-related side effects. Other NRTIs Increased creatine phosphokinase (CPK) activity, myalgia, myositis, and, rarely, rhabdomyolysis have been reported with HIV protease inhibitors, especially in combination with NRTIs. Non-nucleoside reverse transcriptase inhibitors(NNRTIs)Nevirapine There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during concomitant use of nevirapine and lopinavir / ritonavir. The results of a study involving HIV-positive children showed a decrease in lopinavir concentrations during concomitant use with nevirapine.It is believed that the effect of nevirapine on HIV-positive adult patients may be similar to that in children, which may lead to a decrease in the concentration of lopinavir. The clinical significance of the pharmacokinetic interaction is unknown. Lopnavir / ritonavir in combination with nevirapine should not be used once a day. Efavirenz Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg twice daily does not affect the concentration of lopinavir in blood plasma in comparison with the use of lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Increasing the dose of lopinavir/ritonavir tablets to 600/150 mg (six (6) 100/25 mg tablets) twice daily when co-administered with efavirenz significantly increased plasma concentrations of lopinavir by approximately 36% and ritonavir concentrations by approximately 56% to 92% compared to the dose of lopinavir/ritonavir tablets 400/100 mg (four (4) 100/25 mg) when taken twice daily without efavirenz. Efavirenz and nevirapine induce the CYP3A isoenzyme and, thus, can reduce the plasma concentrations of other HIV protease inhibitors when used in combination with lopinavir/ritonavir. Lopnavir / ritonavir with efavirenz should not be taken once a day. Delavirdindelavnrdine is able to increase the concentration of lopinavir in plasma. Protease inhibitors VICAmprenavir Lopinavir/ritonavir may increase the concentration of amprenavir (taking amprenavir at a dose of 750 mg twice daily plus lopnavir / ritonavir leads to an increase in AUC, similar to Cmax, an increase in Cmin relative to amprenavir at a dose of 1200 mg twice daily). Concomitant use of lopinavir / ritonavir and amprenavir reduces the concentration of lopinavir (see section “Dosage and use”). Lopinavir / ritonavir in combination with amprenavir should not be taken once a day. Fosamprenavir A study has shown that concomitant use of lopinavir/ritonavir with fosamprenavir reduces the concentrations of fosamprenavir and lopinavir. Adequate safety and efficacy doses of fosamprenavir and lopinavir/ritonavir in combination have not been established. Concomitant use of elevated doses of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients who had previously received antiretroviral therapy resulted in an increased incidence of gastrointestinal side effects and increased triglyceride concentrations in the combined regimen without increasing antiviral efficacy compared to standard doses of fosamprinavir/ritonavir. Concomitant use of these two drugs is not recommended. Indinavir / ritonavir may increase the concentration of indinavir (when combined with indinavir at a dose of 600 mg twice a day, when used simultaneously with lopinavir/ritonavir, there is a decrease in Cmax, an increase in Cmin compared to taking indinavir three times a day at a dose of 800 mg, while AUC is similar). The indinavir dose may need to be reduced when lopinavir/ritonavir is co-administered 400/100 mg twice daily. use of lopinavir / ritonavir in combination with indinavir once daily has not been studied. Nelfinavir Lopinavir / ritonavir may increase the concentrations of nelfinavir and the nelfinavir metabolite M8 (when taking nelfinavir 1000 mg twice daily and lopinavir/ritonavir compared to taking nelfinavir 1250 mg twice daily, similar AUC, similar Cmax and increased Cmin are observed). Concomitant use of lopinavir / ritonavir and nelfinavir leads to a decrease in lopinavir concentrations. Lopinavir / ritonavir in combination with nelfinavir should not be taken once a day. Ritonavir When used with lopinavir / ritonavir with an additional 100 mg of ritonavir twice daily, the AUC of lopinavir increased by 33%, Cmin increased by 64% compared to lopinavir / ritonavir 400/100 mg. Saquinavir / lopnavir / ritonavir increases saquinavir concentrations (saquinavir 800 mg twice daily plus lopnavir / ritonavir compared to saquinavir 1200 mg three times daily leads to increased AUC, Cmax and Cmin). The dose of saquinavir co-administered with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. use of lopinavir / ritonavir in combination with saquinavir in a once-daily dosage regimen has not been studied. Tipranavir: When tipranavir (500 mg twice daily) was co-administered with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily), there was a 47% and 70% reduction in lopinavir AUC and Cmin, respectively. Therefore, concomitant use of lopinavir / ritonavir and tipranavir with a low dose of ritonavir is not recommended. Other drugsnarcotic analgesicsi Fentanyl: Since lopnavir / ritonavir inhibits the CYP3A4 isoenzyme, it is possible to increase the concentration of fentanyl in blood plasma. Therapeutic and side effects (including respiratory depression) should be carefully monitored when lopinavir/ritonavir and fentanyl are co-administered. Antiarrhythmic drugs (amiodarone, bepridil, lidocaine (systemically) and quinidine)When used concomitantly with lopinavir / ritonavir, their concentrations may increase. Caution should be exercised when using drugs and monitoring therapeutic concentrations, if possible. A digoxin analysis of the literature showed that concomitant use of ritonavir (300 mg every 12 hours) and digoxin resulted in a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin with adequate control of serum digoxin concentrations. Anticancer drugs (e. g. dasatinib, nilotinib, vincristine, vinblastine)It is possible to increase their serum concentrations when used simultaneously with lopinavir/ritonavir, which can lead to side effects usually associated with these antitumor drugs. Anticoagulants may affect warfarin concentrations when used concomitantly with lopinavir/ritonavir. It is recommended to monitor the INR (International Normalized ratio). Antidepressantbupropion Simultaneous use of bupropnone with lopinavir / ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, then it should be carried out under close clinical monitoring of the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism. Simultaneous use of ritonavir and trazodone may lead to an increase in the concentration of trazodone. Side effects were observed: nausea, dizziness, hypotension and fainting. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, should be used with caution and reduce the dose of trazodone. Anticonvulsants (phenobarbital, phenytoin, carbamazepine)It is known that these drugs can induce the CYP3A4 isoenzyme and, thus, reduce the concentration of lopinavir. Lopnavir / ritonavir should not be used once daily in combination with phenobarbital, phenytoin or carbamazepine. In addition, concomitant use of phenytoin and lopinavir / rntonavir results in moderate decreases in steady-state phenytoin concentrations. Phenytoin concentrations should be monitored when the drug is administered concomitantly with lopinavir / ritonavir. Antifungal drugs Ketoconazole, Itraconazole Serum concentrations of ketoconazole and itraconazole may increase under the influence of lopinavir/ritonavir. High doses of ketoconazole and itraconazole (more than 200 mg/day) are not recommended. Voriconazole A study has shown that concomitant use of ritonavir at a dose of 100 mg every 12 hours reduces the steady-state AUC of voriconazole by an average of 39%; therefore, concomitant use of lopinavir/ritonavir and voriconazole should be avoided. Antibacterial drugs A moderate increase in the AUC of clarithromycin has been observed when used concomitantly with lopinavir/ritonavir. The dose of clarithromycin should be reduced in patients with renal or hepatic insufficiency. Anti-TB drugs Rifabutin When rifabutin and lopinavir/ritonavir were co-administered for ten days, the Cmax and AUC of rifabutin (unchanged drug and active 25-O-deacetyl metabolite) increased 3.5-fold and 5.7-fold, respectively. Based on these data, it is recommended to reduce the dose of rifabutin by 75% (i. e. 150 mg every other day or three times a week) when used with lopinavir/ritonavir. Further dose reduction of rifabutin may be necessary. Rifampicin Due to a significant decrease in the concentration of lopinavir, rifampicin should not be taken in combination with the standard dose of lopinavir/ritonavir. The use of rifampicin with a standard dose of lopinavir / ritonavir may lead to a loss of virological response and possible development of resistance to lopinavir/ritonavir or to a class of HIV protease inhibitors or other antiretroviral drugs used simultaneously. An increase in ALT and ACT activity has been observed in studies with higher doses of lopinavir/ritonavir co-administered with rifampicin, and this phenomenon may depend on the dose sequence. When used concomitantly, standard doses of lopinavir/ritonavir should be initiated within approximately 10 days prior to rifampicin use. The dose of lopinavir/ritonavir should be increased. Careful monitoring of liver function is recommended. Antiparasitic agents may reduce the therapeutic concentration of atovaxone when used concomitantly with lopinavir/ritonavir. It may be necessary to increase the doses of atovahone. The glucocorticosteroid hexamethasone may induce the CYP3A4 isoenzyme and may decrease lopinavir concentrations.Fluticasone: concomitant use of lopinavir / ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and lower serum cortisol concentrations. Use with caution. It is recommended to consider alternatives to fluticasone, especially for long-term use. Systemic effects of glucocorticosteroids, including Itsenko-Cushing syndrome and adrenal suppression, have been reported when ritonavir is co-administered with fluticasone by inhalation or nasal use. Similar results were observed with concomitant use of lopinavir / ritonavir and other inhaled glucocorticosteroids that are metabolized similarly to fluticasone, such as budesonide. Special care should be taken when lopinavir/ritonavir is co-administered with any of the inhaled or nasal glucocorticosteroids. Consideration should be given to reducing the dose of glucocorticosteroid with careful monitoring of local and general reactions, or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (e. g. Beclomethasone). Also, in case of discontinuation of glucocorticoid therapy, a gradual dose reduction should be carried out over a long period. Dihydropyridine blockers of “slow” calcium channels (for example, felodipine, nifedipine, nicardipine). There may be an increase in serological concentrations of these drugs when taking lopinavir/ritonavir. Medications taken for erectile dysfunction (phosphodiesterase 5 (PDE-5) inhibitors)Special care should be taken when using sildenafil, tadalafil for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir. Concomitant use of lopinavir/rntonavir with these drugs can significantly increase their concentrations, which can lead to an increased frequency of side effects, such as hypotension and prolonged erection. Sildenafil: use sildenafil with caution for the treatment of erectile dysfunction in reduced doses of 25 mg every 48 hours with special control of side effects. Concomitant use of sildenafil with lopinavir / ritonavir is contraindicated in patients with pulmonary hypertension. Tadalafil: use tadalafil with caution in reduced doses, no more than 10 mg every 72 hours, with careful monitoring of side effects. Vardenafil: concomitant use is contraindicated. Concomitant use of drugs containing St. John’s wort is contraindicated in patients receiving treatment with lopinavir/ritonavir, as this combination may contribute to a decrease in plasma concentrations of lopinavir/ritonavir. This effect may occur due to the induction of the CYP3A4 isoenzyme and may lead to a loss of therapeutic effect and the development of resistance. HMG-CoA reductase inhibitors Plasma concentrations of HMG-CoA reductase inhibitors that are highly dependent on the metabolism of the CYP3A4 isoenzyme, such as lovastatin and simvastatin, can significantly increase when used concomitantly with lopinavir/ritonavir. Since an increase in the concentration of HMG-CoA reductase inhibitors may contribute to the development of myopathy, including rhabdomyolysis, concomitant use with lopinavir / ritonavir is not recommended. Concomitant use of lopinavir / ritonavir with lovastatin and simvastatin is indicated. The metabolism of atorvastatin and rosuvostatin is less dependent on the CYP3A isoenzyme. When using atorvastatin simultaneously with lopinavir/ritonavir, an average of 4.7-fold increase in Cmax and 5.9-fold AUC of atorvastatin was observed, and when using rosuvostatin simultaneously with lopinavir/ritonavir, a 2-fold increase in AUC and 5-fold Cmax were observed. Therefore, in combination with lopinavir/ritonavir, the lowest doses of atorvastatin and rosuvostatin should be used. The results of the drug interaction study of lopinavir / ritonavir and pravastatin did not show a clinically significant interaction. The metabolism of pravastatin and fluvastatin does not depend on the CYP3A4 isoenzyme, so these drugs do not interact with lopinavir/ritonavir. If treatment with a HMG-CoA reductase inhibitor is indicated, the use of pravastatin or fluvastatin is recommended. Immunosuppressant concentrations of these drugs (e. g., cyclosporine, tacrolimus, and sirolimus) may increase when used concomitantly with lopinavir / ritonavir. More frequent monitoring of therapeutic concentrations is recommended until the concentrations of these drugs in the blood are stabilized. Methadone Lopinavir/ritonavir has been shown to reduce plasma concentrations of methadone. Monitoring of methadone plasma concentrations is recommended. Buprenorphine buprenophrine at a dose of 16 mg once a day does not require a dose change. Oral contraceptives or patch-based contraceptives Since ethinyl estradiol concentrations may be reduced when lopinavir/ritonavir is co-administered with estrogen-based oral contraceptives or patch-based contraceptives, alternative or complementary contraceptive measures should be taken. Drugs with which clinically significant interactions are not expected. Drug interaction studies do not show a clinically significant interaction with desipramine, omeprazole, or ranitidine. Based on known metabolic profiles, there are no clinically significant drug interactions between Kaletra® and fluvastatin, dapsone, trimethoprim / sulfamethoxazone, azithromycin, or fluconazole in patients with normal liver and kidney function.

How to take, course of use and dosage

Adult patientsrecommended oral dose of Kaletra® is:

• Four tablets of Kaletra ® 100/25 mg (400/100 mg) twice a day, regardless of food intake.
• Eight tablets of Kaletra ® 100/25 mg (800/200 mg) once a day, regardless of food intake, for patients with less than 3 mutations associated with the development of resistance to lopinavir. There are insufficient data for the use of lopinavir / rntonavir once daily in adult patients with 3 or more mutations associated with the development of resistance to lopinavir.

Concomitant therapy The use of Kaletra tablets in combination with omeprazole and ranntndine does not require dose adjustment. In patients with suspected low sensitivity to lopinavir (clinically or in the laboratory) who have previously received antiretroviral therapy, the dose of Kaletra tablets should be increased in combination with efavirenz, nevirapine, amprenavir or nelfinavir. up to 500/125 mg (5 tablets of 100/25 mg) 2 times a day. When used concomitantly with these drugs, Kaletra®tablets do not use it once a day. The children’s mode of taking Kaletra tablets once a day in children has not been studied. An adult dose of Kaletra ® tablets (400/100 mg twice daily) without concomitant use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children with a body weight of 35 kg or more or with a body surface area of 1.4 m2 or more. It is recommended to use the following tables to determine the dose for children with a body weight of less than 35 kg or with a BMI of 0.6 to 1.4 m2. For children with a PTA of less than 0.6 m or for children under 3 years of age, there is a solution of Kaletra® for oral use. Tables 1 and 2 provide guidelines for the dosage of Kaletra®® 100/25 mg tablets, based on the RTA.

Overdose

Currently, the clinical experience of acute overdose with lopinavir/ritonavir in humans is limited. There is no special antidote. Treatment should include general supportive care, including monitoring of vital signs and monitoring the patient’s clinical status. If necessary, remove the unabsorbed drug by gastric lavage and prescribe activated charcoal. Since lopnavir / ritonavir is highly bound to plasma proteins, the use of dialysis is impractical.

Special instructions

Hepatic insufficiencylopinavir/ritonavir is primarily metabolized by the liver. Therefore, special care should be taken when using this medicine in patients with reduced liver function. Lopinavir / ritonavir has not been studied in patients with severe hepatic insufficiency. Pharmacokinetic data show an increase in plasma concentrations of lopinavir by approximately 30%, as well as a decrease in the degree of binding to plasma proteins in patients simultaneously infected with HIV and hepatitis C virus and mild to moderate hepatic insufficiency. Patients with underlying hepatitis B or C disease or significant increases in hepatic transaminase activity prior to treatment may be at increased risk for further increases in transaminase activity. Since the drug’s introduction to the market, there have been cases of hepatic dysfunction, including several deaths, which mainly occurred among patients with advanced HIV infection who were simultaneously taking drugs to treat the underlying disease, such as chronic hepatitis or cirrhosis. A causal relationship with lopinavir / ritonavir treatment has not been established. In these patients, more careful monitoring of AST/ALT activity is necessary, especially during the first few months of treatment with lopinavir / ritonavir.Diabetes mellitus / hyperglycemia In the primary diagnosis of diabetes mellitus, exacerbation of previously diagnosed diabetes mellitus and hyperglycemia have been reported in post-marketing observations in HIV-positive patients treated with HIV protease inhibitors. Some patients required prescribing or adjusting the dose of insulin or oral hypoglycemic drugs. Diabetic ketoacidosis has been reported in some cases. In those patients who stopped treatment with HIV protease inhibitors, hyperglycemia sometimes persisted. Since these effects were reported voluntarily during clinical practice, it is not possible to estimate the frequency of these effects and establish a causal relationship between treatment with HIV protease inhibitors and these effects. PANCREATITIS in patients treated with lopinavir/ritonavir, cases of pancreatitis have been reported, including in those patients who experienced significant increases in triglyceride concentrations. Fatal cases have been reported. Although a causal relationship with lopinavir/ritonavir has not been established, a significant increase in triglyceride concentrations is a risk for pancreatitis. Patients with advanced HIV infection may be at an increased risk of increased triglyceride concentrations and developing pancreatitis, and patients with a history of pancreatitis may be at risk of developing recurrent pancreatitis during treatment with lopinavir/ritonavir. Increased bleeding, including spontaneous formation of subcutaneous hematomas and development of hemarthrosis, has been reported in patients with type A and B hemophilia treated with HIV protease inhibitors. Some patients were prescribed additional doses of coagulation factor VIII. In more than half of the reported cases, treatment with HIV protease inhibitors was continued or started again. A causal relationship or mechanism of action between treatment with HIV protease inhibitors and these events has not been established. Prolongation of the PR interval When taking lopinavir / ritonavir, some patients showed a moderate asymptomatic prolongation of the PR interval. When taking lopinavir/ritonavir, cases of second-and third-degree atrioventricular block have rarely been reported in patients with organic heart disease and pre-existing disorders of the cardiac conduction system or in patients taking drugs that extend the PR interval (such as verapamil or atazanavir). Lopinavir / ritonavir should be used with caution in these patients. Electrocardiogram QTcF interval (adjusted for Fridericia) was evaluated in a randomized, placebo-controlled cross – sectional study with active control (moxnfloxacin 400 mg once daily) in 39 healthy adult volunteers. 10 measurements were performed for 12 hours on day 3 of the study. The mean maximum difference in QTcF compared to placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for the 400/100 mg twice daily and 800/200 mg twice daily doses of lopinavir/ritonavir, respectively. The changes observed when taking the above two regimens were approximately 1.5 and 3 times higher than those observed when taking the recommended doses of lopinavir/ritonavir once a day or twice a day at steady state. None of the patients showed an increase in the QTcF interval > 60 ms compared to the baseline value; the QTcF interval did not exceed the potentially clinically significant threshold of 500 ms. In the same study, a moderate increase in the PR interval was also observed in patients taking lopinavir/ritonavir on day 3. The maximum PR interval was 286 ms, and there was no development of grade II or III atrioventricular block. Adipose tissue redistrib Utiondistribution/accumulation of adipose tissue, including central obesity, increased adipose tissue deposition in the dorsocervical region (“bull’s hump”), peripheral exhaustion (decreased adipose tissue in the extremities), facial exhaustion, chest enlargement, and “kushingoid appearance”, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these effects are currently unknown. No causal relationship was established. Increased lipid concentrations between lopinavir / ritonavir may lead to increased cholesterol and triglyceride concentrations. Triglyceride and cholesterol concentrations should be evaluated before starting lopinavir / ritonavir and periodically during treatment. If necessary, appropriate treatment of lipid metabolism disorders should be carried out with immunity restoration syndrome. HIV-infected patients receiving combined antiretroviral therapy, including lopnavir/ritonavir, have experienced the development of immunity restoration syndrome. When immune function is restored at the beginning of combined antiretroviral therapy, asymptomatic or residual opportunistic infections (infection caused by Mycobacterium avium and/or Pneumocystis jiroveci, cytomegalovirus infection, pneumonia, or tuberculosis) may worsen, which may require additional examination and treatment. Osteonecrosis It is known that many factors play a role in the etiology of osteonecrosis (taking corticosteroids, alcohol abuse, high body mass index, severe immunosuppression, etc. ), in particular, cases of osteonecrosis have been reported in patients with progressive HIV infection and/or long-term use of combined antiretroviral therapy. Therefore, these patients should be advised to consult a doctor if they experience pain, stiffness in the joints and impaired motor function. Taking the drug in elderly patients Clinical studies of lopinavir/ritonavir did not include patients older than 65 years and more, in sufficient numbers to determine the characteristics of responses for this age category. Caution should be exercised when using lopinavir/ritonavir in elderly patients, given the increased incidence of decreased liver, kidney or heart function, comorbidities, and concomitant therapy. Use in children and HIV-infected patients under 12 years of age, the pattern of side effects observed during the clinical trial was similar to that in adult patients. Evaluation of the antiviral activity of lopinavir/ritonavir in children continues in clinical trials. Lopinavir/rntonavir once-daily dosing regimen was not evaluated in paediatric patients. However, as the drug concentration increases, glucose tolerance decreases. Influence on the ability to drive motor vehicles, manage mechanisms. During treatment, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions, as the drug can cause dizziness and other side effects that may affect these abilities. Studies of the ability to drive motor vehicles and manage mechanisms have not been conducted.

Storage conditions

At a temperature of 15 to 30 °C. Keep out of reach of children.

Active ingredient

Lopinavir, Ritonavir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets